Opiates have been suggested as having a role in the pathogenesis of HIV infection among intravenous (IV) drug users. Reports of opiate-induced suppression of cell-mediated immunity are consistent with this suggestion; however, studies are needed that directly investigate the biological consequences of opiate effects on the immune system. In this grant application, experiments are proposed to test the hypothesis that opiates promote the pathogenesis of intracellular microorganisms and thus could act as a cofactor in AIDS. Two approaches will be taken, one involving in studies of HIV (the primary etiologic agent of AIDS) and the other involving murine models of infection with Toxoplasma gondii ( a cause of serious opportunistic infection in HIV-infected patients). The aims of our proposed in vitro studies have evolved from preliminary studies, which demonstrate that morphine markedly enhances the growth of HIV in cocultures of human peripheral blood mononuclear cells (PBMNC). Specifically, we will use a PBMNC coculture assay system, as well as purified monocyte and T-cell lines to: 1) define the mechanisms whereby morphine enhances HIV replication, 2) determine whether other opioids also promote HIV growth, and 3) investigate the interactive effects of cocaine and morphine. The T.gondii studies we are proposing have their genesis in preliminary observations that morphine-addicted mice have a strikingly increased mortality following T. gondii infection. Murine models of toxoplasmosis, in which the contribution of cell-mediated immunity to host defense has been well defined, will be employed to: 1) determine the mechanisms involved in morphine-induced lethality of acute T. gondii infection, and 2) determine the impact of morphine addiction on latent central nervous system toxoplasmosis. Finally, PBMNC will be obtained from methadone-maintenance treatment patients to determine whether these cells, which are chronically exposed in vivo to an opiate, will promote the growth of HIV or T. gondii in vitro; at the same time, PBMNC obtained from asymptomatic HIV seropositive patients will be cultured in the presence of morphine to ascertain whether exposure to an opiate facilitates the growth of T. gondii. The long term goal of the studies outlined in this proposal is to improve our understanding of the immunopathogenesis of HIV infection in opiate addicts, and thereby to derive new approaches to interfere with the development of AIDS in the IV drug user population.